Substituted heteroarylphenyloxazolidinones

ABSTRACT

The present invention discloses novel substituted aryl- and heteroarylphenyloxazolidinones which are useful as anti-bacterial agents. More specifically, the substituted aryl- and heteroarylphenyloxazolidinones of the invention are characterized by oxazolidinones having an aryl or heteroaryl group at the p-position of the 3-phenyl ring and additional substitutions at the m-position(s) of the 3-phenyl ring. A compound representative of this new class of oxazolidinones is (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present patent application is a divisional of U.S. patentapplication Ser. No. 08/466,955, filed Jun. 6, 1995, now U.S. Pat. No.5,801,246 which is a divisional of U.S. patent application Ser. No.08/233,903 filed Apr. 28, 1994, now U.S. Pat. No. 5,565,571 which was acontinuation application of PCT application PCT/US92/08267, filed Oct.5, 1992, which was a continuation-in-part application of U.S. patentapplication Ser. No. 07/831,213, filed Feb. 7, 1992 (now abandoned)which was a continuation-in-part application of U.S. patent applicationSer. No. 07/786,107, filed Nov. 1, 1991 (now abandoned).

FIELD OF THE INVENTION

The present invention relates to novel substituted aryl- andheteroarylphenyloxazolidinones which are useful as anti-bacterialagents.

BACKGROUND OF THE INVENTION

The oxazolidinones are a class of orally-active, synthetic antibacterialagents. 3-Phenyl-2-oxazolidinones having one or two substitutions on thephenyl ring are known. For one substitution see U.S. Pat. Nos.4,948,801, 4,461,773, 4,340,606, 4,476,136, 4,250,318, 4,128,654, Re29,607, EP Publication 0 312 000, J. Med. Chem., 32, 1673 (1989), J.Med. Chem., 33, 2569 (1990) and Tetrahedron, 45, 1323 (1989). Compoundsof this type include the antibacterial DuP 721, see J. Med. Chem., 32,1673 (1989).

3- (di- or fused-ring substituted)phenyl!-2-oxazolidinones are reportedin U.S. Pat. Nos. 4,977,173, 4,921,869 and 4,801,600; EP Publications 0316 594, 0 184 170, and 0 127 902; and U.S. Pat. No. 5,164,510 andW091/07409.

The present invention is 3- (di- andtri-substituted)phenyl!-2-oxazolidinones which are effective asantibacterial agents. The compounds of the invention are characterizedby oxazolidinones having an aryl or heteroaryl group at the p-positionof the 3-phenyl ring and additional substitution(s) at the m-position ofthe phenyl ring with radicals having an electron-withdrawing effect.These compounds are surprisingly effective as antibacterial agents,since early work by Gregory, et al, in J. Med. Chem., 33, 2569 (1990)suggests compounds having such radicals in the p-position of the phenylring are less effective antibacterial agents.

Synthesis of 3-phenyl-2-oxazolidinones and derivatives thereof are wellknown in the art. However, due to the nature of the radicals, thesubstituted phenyls of the invention are difficult to synthesize. Thus,we also disclose a process by which the compounds of the invention maybe synthesized.

INFORMATION DISCLOSURE

The following references disclose 3-phenyl-2-oxazolidinones having asingle substitution on the phenyl ring:

U.S. Pat. No. 4,948,801 discloses 3- (aryl andheteroaryl)phenyl!-2-oxazolidinones having antibacterial activity.

U.S. Pat. No. 4,476,136 discloses 3- (p-arylalkyl, arylalkenyl, andarylacetylenic substituted)phenyl!-5-(aminomethyl)-2-oxazolidinoneswhich have antibacterial activity.

U.S. Pat. No. 4,461,773 discloses substituted3-phenyl-5-(hydroxymethyl)-2-oxazolidinones which have antibacterialactivity.

U.S. Pat. No. 4,340,606 discloses substituted 3-(p-alkylsulfonyl)phenyl!-5-(hydroxymethyl)- or(acyloxymethyl)-2-oxazolidinones having antibacterial activity inmammals.

U.S. Pat. No. 4,250,318 discloses substituted3-phenyl-5-(hydroxyrnethyl)-2-oxazolidinones having antidepressiveutility.

U.S. Pat. No. 4,128,654 discloses substituted3-phenyl-5-(halomethyl)-2-oxa-zolidinones which are useful incontrolling fungal and bacterial diseases of plants.

U.S. Reissue Pat. No. 29,607 discloses substituted 3phenyl-5-(hydroxymethyl)-2-oxazolidinones having antidepressive,tranquilizing and sedative utility.

Belgian Patent 892,270 discloses the 3- (arylalkyl, arylalkenyl orarylacetylenic substituted)phenyl!-5-(aminomethyl)-2-oxazolidinonescorresponding to U.S. Pat. No. 4,476,136 listed above.

European Patent Publication 0 352 781 discloses aryl and heteroarylsubstituted 3-phenyl-2-oxazolidinones corresponding to U.S. Pat. No.4,948,801 listed above.

European Patent Publication 0 312 000, as reported in Chemical Abstracts89-116142/16, discloses phenylmethyl and pyridinylmethyl substituted3-phenyl-2-oxazolidinones.

J. Med. Chem. 33, 2569 (1990) and J. Med. Chem. 32, 1673 (1989);Tetrahedron 45, 1323 (1989); and Antimicrobial Agents and Chemotherapy1791 (1987) are additional recent references disclosing 3-(p-substituted) phenyl!-2-oxazolidinones.

The following references disclose 3- (di-substituted)phenyl!- or 3-(fused-ring substituted)phenyl!-2-oxazolidinones:

U.S. Pat. No. 4,977,173 discloses 3-phenyl-2-oxazolidinones having alactam at the p-position and fluorine at the m-position of the phenylring (Formula XIII). However, the 3- (di- ortri-substituted)phenyl!-2-oxazolidinones of the present invention havean aromatic ring at the p-position.

U.S. Pat. Nos. 4,921,869 and 4,801,600 disclose 6'-indolinyl- oralkanoneoxa-zolidinones where the indolinyl nitrogen is meta (m-) to theoxazolidinone nitrogen.

U.S. Pat. No. 4,705,799 discloses substituted aminomethyloxooxazolidinylbenzene derivatives including sulfides, sulfoxides, sulfones andsulfonamides which possess antibacterial activity. However, compounds ofthe present invention have an aryl or heteroaryl at the p-position ofthe phenyl ring.

European Patent Publication 0 316 594 discloses substituted3-(styryl)-2-oxazolidinones corresponding to U.S. Pat. No. 4,977,173listed above.

European Patent Publications 0 184 170 and 0 127 902 correspond to U.S.Pat. No. 4,705,799, discussed above.

U.S. Pat. No. 5,164,510 and WO91/07409 disclose 3- (fused-ringsubstituted)-phenyl!-2- oxazolidinones which are useful as antibacterialagents.

The above references do not disclose the 3- (di- ortri-substituted)phenyl!-2-oxazolidinones of the present invention.

SUMMARY OF THE INVENTION

Disclosed are substituted aryl- and heteroaryl-phenyl oxazolidinones ofFormula (XII) ##STR1## where

(I) R₁ and R₂ are the same or different and are selected from the groupconsisting of

(a) --H,

(b) --F,

(c) --Cl,

(d) --CF₃, and

(e) --OCH₃, provided that only one of R₁ or R₂ may be hydrogen;

(II) R₃ is selected from the group consisting of

(a) phenyl,

(b) pyridyl,

(c) pyrazinyl, (d) pyridazinyl, (e) pyrimidinyl,

(f) 1,2,3-, (g) 1,2,4-, (h) 1,2,5-triazinyl,

(i) quinolinyl, (j) isoquinolinyl,

(k) quinoxalinyl, (l) quinazolinyl, (m) phthalazinyl, (n) cinnolinyl,

(o) naphthyridinyl,

(p) indolyl having nitrogen optionally substituted with R₅₋₁ where R₅₋₁--H,

C₁ -C₄ alkyl optionally substituted with one or more halogens,

C₃ -C₆ cycloalkyl, or

--C(O)R₅₋₂ where R₅₋₂ is --H,

C₁ -C₄ alkyl optionally substituted with one or more halogens, or

phenyl optionally substituted with one or more halogens,

(q) pyrrolopyridinyl having the saturated nitrogen substituted with R₅₋₁where R₅₋₁ is as defined above, (r) furanopyridinyl, (s)thienopyridinyl,

(t) benzothiazolyl, (u) benzoxazolyl,

(v) imidazolyl having the saturated nitrogen substituted with R₅₋₁ whereR₅₋₁ is as defined above,

(w) pyrazolyl having the saturated nitrogen substituted with R₅₋₁ whereR₅₋₁ is as defined above,

(x) thiazolyl, (y) isothiazolyl,

(z) oxazolyl, (aa) isoxazolyl,

(bb) pyrroyl having nitrogen substituted with R₅₋₁ where R₅₋₁ is asdefined above,

(cc) furanyl, (dd) thiophenyl, wherein substitutents (a)-(dd) areoptionally substituted with X and Y,

(ee) 1,2,3-, (ff) 1,2,4-triazolyl having the saturated nitrogensubstituted with R₅₋₁ where R₅₋₁ is as defined above, whereinsubstituents (ee) and (ff) are optionally substituted with X;

(III) each occurrence of Y is independently selected from

(a) --H,

(b) --F, (c) --Cl, (d) --Br, (e) --I,

(f) --R₃₋₁, (g) --OR₃₋₁, where R₃₋₁ is H or C₁ -C₄ alkyl, or

(h) --NO₂ ;

(IV) each occurrence of X is independently selected from

(a) --H,

(b) C₁ -C₈ alkyl optionally substituted with one or more halogens,

--OH,

═O other than at alpha position,

--S(O)_(n) R₃₋₂ where R₃₋₂ is C₁ -C₄ alkyl or C₃ -C₈ cycloalkyl, or

--NR₃₋₃ R3-4 where R₃₋₃ and R₃₋₄ are the same or different and are --H,C₁ -C₈ alkyl, C₃ -C₈ cycloalkyl, --(CH₂)_(t) CHOR₃₋₅, --(CH₂)_(t) NR₃₋₆R₃₋₇, or taken together are --(CH₂)O(CH₂)--, --(CH₂)_(t) CH(CO)R₃₋₈, or--(CH₂)N(R₃₋₈)(CH₂)₂ -- where

R₃₋₅ is --H or C₁ -C₄ alkyl, or

R₃₋₆ and R₃₋₇ are the same or different and are --H,

C₁ -C₄ alkyl or taken together are --(CH₂)r--,

(c) C₂ -C₅ alkenyl,

(d) C₃ -C₈ cycloalkyl,

(e) --OR₃₋₃ where R₃₋₃ is as defined above,

(f) --CN,

(g) --S--(O)_(n) --R₃₋₈ where R₃₋₈ is

C₁ -C₄ alkyl optionally substituted with one or more halogens,

--OH,

--CN,

--NR₃₋₃ R₃₋₄ where R₃₋₃ and R₃₋₄ are as defined above, or

--CO₂ R₃₋₅ where R₃₋₅ is as defined above,

C₂ -C₄ alkenyl,

--NR₃₋₉ R₃₋₁₀ where R₃₋₉ is --H, C₁ -C₄ alkyl, or C₃ -C₈ cycloalkyl andR₃₋₁₀ is --H, C₁ -C₄ alkyl, C₁ -C₄ alkenyl, C₃ -C₄ cycloalkyl, --OR₃ 5,or --NR₃₋₆ R₃₋₇ where R₃₋₅, R₃₋₆, and R₃₋₇ are as defined above,

--N₃,

--NHC(O)R₃₋₁₁ where R₃₋₁₁ is C₁ -C₄ alkyl optionally substituted withone or more halogens,

(h) --S(O)₂ --N═S(O)_(p) R₃₋₁₄ R₃₋₁₅ where R₃₋₁₄ and R₃₋₁₅ are the sameor different and are C₁ -C₂ alkyl, or taken together are --(CH2)_(q) --,

(i) --S--C(O)--R₃₋₁₁ where R₃₋₁₁ is as defined above,

(j) tetrazoly,

(k) --NR3-3R₃₋₄ where R₃₋₃ and R₃₋₄ are as defined above,

(l) --N(R₃₋₃)COR₃₋₁₁ where R₃₋₃ and R₃₋₁₁ are as defined above,

(m) --N(R₃₋₃)S(O)_(n) R₃₋₁₁ where R₃₋₃ and R₃₋₁₁ are as defined above,

(n) --CONR₃₋₃ R₃₋₄ where R₃₋₃ and R₃₋₄ are as defined above,

(o) --C(O)R₃₋₁₆ where R₃₋₁₆ is --H,

C₁ -C₈ alkyl optionally substituted with one or more halogens,

C₁ -C₄ alkyl optionally substituted with

--OR₃₋₅,

--OC(O)R₃₋₅,

--NR₃₋₃ R₃₋₄,

--S(O)_(n) R₃₋₁₇,

C₃ -C₈ cycloalkyl, or

C₂ -C₅ alkenyl optionally substituted with --CHO or --CO₂ R₃₋₅,

where R3-3, R₃₋₄, and R₃₋₅ are as defined above and R₃₋₁₇ is C₁ -C₄alkyl or C₃ -C₈ cycloalkyl,

(p) --C(═NR3-18)R₃₋₁₆ where R₃₋₁₆ is as defined above and R₃₋₁₈ is--NR₃₋₃ R₃₋₄, --OR₃₋₃, or --NHC(O)R₃₋₃ where R₃₋₃ and R₃₋₄ are asdefined above,

(q) --CR₃₋₁₆ (OR₃₋₁₉)OR₃₋₂₀ where R₃₋₁₆ is as defined above and R₃₋₁₉and R₃₋₂₀ are the same or different and are C₁ -C₄ alkyl, or takentogether are --(CH₂)m--, ##STR2## where R₃₋₃, R₃₋₄, R₃₋₅, R₃₋₉, andR₃₋₁₆ are as defined above and R₃₋₂₁ is R₃₋₄ or --NR₃₋₄ R₃₋₅ where R₃₋₄and R₃₋₅ are as defined above;

m is 2 or 3;

n is 0, 1, or 2;

p is 0 or 1;

q is 3, 4, or 5;

t is 1, 2, or 3;

(V) R₄ is selected from the group consisting of

(a) --H,

(b) C₁ -C₁₂ alkyl optionally substituted with 1-3 Cl,

(c) C₃ -C₁₂ cycloalkyl,

(d) C₅ -C₁₂ alkenyl containing one double bond,

(e) phenyl optionally substituted with 1-3 --OH, --OCH₃, --OC₂ H₅,--NO₂, --F, --Cl, --Br, --COOH and --SO₃ H, --N(R₄₋₁)(R₄₋₂) where R₄₋₁and R₄₋₂ are the same or different and are --H and C₁ -C₅ alkyl,

(f) furanyl,

(g) tetrahydrofuranyl,

(h) 2-thiophene,

(i) pyrrolidinyl,

(k) pyridinyl,

(k) --O--R₄₋₃ where R₄₋₃ is C₁ -C₄ alkyl,

(l) --NH₂,

(m) --NHR₄₋₄ where R₄₋₄ is C₁ -C₃ alkyl or --φ,

(n) --NR₄₋₄ R₄₋₅ where R₄₋₄ is as defined above and R₄₋₅ is C₁ -C₃alkyl, or taken together with the attached nitrogen atom to form asaturated mononitrogen C₅ -C₇ heterocyclic ring including --O--(morpholine),

(o) --CH₂ --OH,

(p) --CH₂ --OR₄₋₆ where R₄₋₆ is C₁ -C₄ alkyl or --CO--R₄₋₇ where R₄₋₇ isC₁ -C₄ alkyl or --φ;

and pharmaceutically acceptable salts thereof.

More particularly, the invention discloses compounds of formula (XII)where R₃ is a pyridyl or phenyl ring which are optionally substitutedwith --H, C₁ -C₄ alkyl, or --R₃₋₃ R₃₋₄,

Most particularly, disclosed are the compounds(±)-5-(acetamidomethyl)-3-4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone and(±)-5-(acetamidomethyl)-3-4-(4-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone.

Another aspect of the invention discloses a process for making acompound of formula (XII) comprising:

(a) converting a substituted aniline to a stabase derivative,

(b) treating the stabase derivative to form an aryl- orheteroaryl-substituted aniline, and

(c) converting the aryl- or heteroaryl-substituted aniline to a aryl- orheteroaryl-substituted phenyloxazolidinone.

More particularly, this aspect of the invention discloses a process formaking a compound of formula (XII) wherein step (b) comprises treatmentof the stabase derivative with an appropriate alkyl- or aryllithium toform a lithiated derivative, transmetallation with an appropriateelectrophilic metal species, addition of an appropriate aryl- orheteroaryl halide or sulfonate precursor in the presence of anappropriate metal catalyst to form a protected aryl- orheteroarylaniline, and removal of the stabase protecting group withaqueous mineral acid.

Most particularly, this aspect of the invention discloses a process formaking a compound of formula (XII) wherein step (b) is carried out in aone-pot reaction sequence involving deprotonation of the stabasederivative with n-butyllithium in tetrahydrofuran to form a lithiatedderivative, transmetallation with zinc chloride, addition of an aryl- orheteroaryl- bromide, iodide, triflate, or fluorosulfonate in thepresence of tetrakis(triphenylphosphine)palladium catalyst to form aprotected aryl- or heteroaryl- aniline, and deprotection with aqueoushydrochloric acid.

Still another aspect of the invention discloses a process for making anoxazolidinone iodide comprising reacting a carbobenzyloxy allyl compoundin the presence of an excess of pyridine and iodine, said excess beingof equal amounts in the range of 2-20 molar equivalents.

More particularly, this aspect of the invention discloses a process formaking an oxazolidinone iodide comprising reacting a carbobenzyloxyallyl compound in the presence of an excess of pyridine and iodine,wherein said excess is in the range of 5-15 molar equivalents.

Most particularly, this aspect of the invention discloses a process formaking an oxazolidinone iodide comprising reacting a carbobenzyloxyallyl compound in the presence of an excess of pyridine and iodine,wherein said excess is in the range of 8-10 molar equivalents.

DETAILED DESCRIPTION OF THE INVENTION

It is preferred that R₁ or R₂ are --F or --CF₃ ; it is most preferredthat R₁ or R₂ are --F.

It is preferred that R₃ is phenyl or pyridyl; it is most preferred thatR₃ is 3-pyridyl or 4-pyridyl.

It is preferred that X is --H, C₁ -C₄ alkyl, or --NR₃₋₃ R₃₋₄ ; it ismost preferred that X is --H.

It is preferred that Y is --H or C₁ -C₄ alkyl; it is most preferred thatY is --H.

It is preferred that R₄ is C₁ -C₅ alkyl optionally substituted with 1-3halogens, C3-C₅ cycloalkyl, --NR₃₋₃ R₃₋₄, and --OR₃₋₃ ; it is mostpreferred that R₄ is --CH₃.

It is preferred that R₅ is C₁ -C₄ alkyl.

The structures of the aryl and heteroaryl groups which comprise R₃(I-XII) are shown in CHART C. Structures (o) (naphthyridinyl), (q)(pyrrolopyridinyl), (r) (furanopyridinyl), and (s) (thienopyridinyl)show the nitrogen-containing heteroaryl abbreviated as Z, where Z is anunsaturated 4-atom linker having one nitrogen and three carbons. In thisway, each of the four possible positions for the heteroaryl nitrogen areencompassed by structures (o), (q), (r), and (s).

The aryl- and heteroaryl-substituted phenyloxazolidinones (XII) of thepresent invention are useful as antibacterial agents in treatinginfections in mammals caused by gram-positive and anaerobic infections.It is preferred to treat humans and warm-blooded mammals such as cattle,horses, sheep, hogs, dogs, cats, etc., with the aryl- andheteroaryl-substituted phenyl oxazolidinones (XII) of the presentinvention.

The aryl- and heteroaryl-substituted phenyloxazolidinones (XII) of thepresent invention are also useful in treating patients infected with oneor more Mycobacterium spp. Of particular interest, the aryl- andheteroaryl-substituted phenyloxazolidinones (XII) of the invention areuseful in treating patients infected with M. tuberculosis and M. avium.

The aryl- and heteroaryl-substituted phenyloxazolidinones (XII) of theinvention can be administered in a manner and in dosage forms similar tothose of the known phenyloxazolidinones described above. For example,administration can be either parenteral (IV, IM, SQ) or oral. The dailydose is about 3 to about 30 mg/kg. This dose can preferably be given individed doses and administered 2-4 times daily. The preferred route ofadministration as well as the particular dosage form for either theparenteral or oral route depends on the particular facts of thesituation including the nature of the infection and condition of thepatient. The usual pharmaceutical dosage forms appropriate forparenteral (mixture, suspension in oil) and oral (tablet, capsule,syrup, suspension, etc) administration are known to those skilled in theart and there is nothing unusual about using those dosage forms with thearyl- and heteroaryl-substituted phenyloxazolidinones (XII). The exactdosage of the aryl- and heteroaryl-substituted phenyloxazolidinones(XII) to be administered, the frequency of administration, route ofadministration, and the dosage form will vary depending on a number offactors known to those skilled in the art including the age, weight,sex, general physical condition of the patient, the nature of theinfection (particular microorganism involved, its virulence, the extentof the infection) other medical problems of the patient, etc., as iswell known to the physician treating infectious diseases.

The aryl- and heteroaryl-substituted phenyloxazolidinones (XII) can beused either alone or in conjunction with other antibacterial agents asis known to those skilled in the art. Further, the aryl- andheteroaryl-substituted phenyloxazolidinones (XII) can be used inconjunction with non-antibacterial agents as is known to those skilledin the art.

Suitable pharmaceutical salts include the acid addition salts when abasic group is present, such as occurs with the preferred pyridyl group.The acid addition salts including those made from mineral acids, e.g.,hydrochloric, hydrobromic, sulfuric, phosphoric, etc., organic sulfonicacids, e.g., methanesulfonic, organic carboxylic acids, e.g., amino, andcarbohydrate acids, e.g., gluconic, galacturonic, etc. It is alsoappreciated by those skilled in the art that the appropriate N-oxides ofR₃ heteroaryls and tertiary amino substituted aryls are included withinthe scope of the aryl- and heteroaryl-substituted phenyloxazolidinones(XII) of the invention.

The pharmaceutically active aryl- and heteroaryl-substitutedphenyloxazolidinones (XII) of this invention are prepared as describedbriefly here and in more detail in the examples which follow. CHART Adescribes the synthesis of the aryl- and heteroaryl-substituted aniline(VI) compounds.

These aniline compounds (VI) are then subsequently reacted followingprocedures known, or readily acquired by one skilled in the art. Thesesubsequent procedures parallel those described in U.S. Pat. No.4,705,799, WO91/07409, U.S. Pat. No. 5,164,510, and J. Med. Chem., 32,1673 (1989), all of which are incorporated herein by reference. TheCardillo-Ohno reaction is discussed in Tetrahedron 43, 2505 (1979) andTetrahedron Lett., 28, 3123 (1987), both of which are also incorporatedherein by reference.

CHART A demonstrates a method of preparation of the aryl- andheteroaryl-substituted anilines of the invention. The starting point isa mono- or disubstituted aniline (I). These materials are readilyavailable from a number of commercial vendors. Alternatively, theanilines (I) are known in the chemical literature and may be readilyprepared by one skilled in the art. The substituted aniline (I) istreated with n-butyllithium and 1,2-bis(chlorodimethylsilyl)ethane toform the stabase (SB) derivative (II). The SB derivative (II) isconverted, in a one-pot reaction sequence, to the crude aryl- andheteroaryl-substituted aniline (VI). This sequence involves slowaddition of n-butyllithium to (II), resulting in the aryllithium (III).The aryllithium (III) is transmetallated with anhydrous zinc chloride intetrahydrofuran (THF) to give an organo zinc derivative (IV).Alternatively, the transmetallation can be carried out withtrimethylborate to give the corresponding boric acid, or withtributyltin chloride to give the corresponding stannane. These speciesreact in a manner analogous to that of the organozinc derivative (IV).Addition of the appropriate aryl or heteroaryl iodide, bromide,trifluoromethane sulfonate (triflate), or fluorosulfonate and palladiumcatalyst, preferably, tetrakis(triphenylphosphine)palladium, followed bywarming to reflux temperature gives the coupled product (V). Thereaction is quenched with aqueous mineral acid, preferably hydrochloric,to give the aryl- or heteroaryl-substituted aniline (VI). The product(VI) may then be further purified following chromatographic techniqueswell known in the art. Alternatively, the chromatographic purificationmay be delayed until after the carbobenzoxy group is appended.

The remaining synthetic steps which lead to the aryl- andheteroaryl-substituted phenyl oxazolidinone (XII) of the invention areoutlined in CHART B and closely parallel the procedure found in thatdiscussed in U.S. Pat. No. 4,705,799, WO91/07409, U.S. Pat. No.5,164,510 and J. Med. Chem., 32, 1673 (1989). Briefly, the aniline (VI)is converted to the carbobenzoxy derivative (VII) in the presence ofbase and THF. Alkylation of (VII) with allyl halide, preferably bromide,gives the allylated product (VIII). This intermediate (VIII) issubjected to a modified Cardillo-Ohno iodocyclocarbamation reactionwherein an excess of pyridine in combination with the iodine, is addedto facilitate formation of the oxazolidinone iodide (IX). Theiodocyclocarbamation reaction as disclosed by Cardillo-Ohno requires 2-3equivalents of iodine (I₂), whereas when synthesizing the compounds ofthe invention an amount of pyridine and iodine is added which is in therange of 2-20 molar equivalents of each compound. Preferably, 5-15equivalents should be employed, most preferred is 8-10 equivalents. Inaddition, we have found that this process has utility in reactions wherebenzyl iodide is formed and the product so formed competes in thereaction for the substrate and/or product to form unwanted benzylatedproducts. This process, then, is useful to improve yields because it isbelieved that the excess pyridine traps the benzyliodide to inhibit thiscompetitive reaction. In the synthesis of the compounds of the inventionan excessive of pyridine is necessary; when pyridine is omitted from thereaction mixture essentially none of the compounds of the invention arerecovered.

After the formation of the iodide (IX) purification may be accomplishedfollowing chromatography procedures known in the art. However, this isnot necessary as the iodide (IX) may be directly converted to thecorresponding azide (X) by treatment with sodium azide in the presenceof DMF. Reduction of (X) in the presence of hydrogen, methanol or ethylacetate, and palladium catalyst affords the amine (XI). Acetylation ofthe amine (XI) provides the aryl-and heteroaryl-substitutedphenyloxazolidinones (XII) of the invention.

The aryl- and heteroaryl-substituted phenyloxazolidinones (XII) of theinvention contain at least one chiral center. It is apparent to oneskilled in the art that when one chiral center is present, the compoundcan exist as one of two possible optical isomers (R) and (S)enantiomers! or a racemic mixture of both. Both individual (R) and (S)enantiomers, as well as mixtures thereof, are within the scope of aryl-and heteroaryl-substituted phenyloxazolidinones (XII) of the invention.In the event a second chiral center is present in the aryl- andheteroaryl-substituted phenyloxazolidinones (XII) of the invention, theresultant diastereomers, in racemic and enantiomerically enriched forms,are also within the scope of the compounds (XII) of the invention.

The enantiomer which is pharmacologically active is the enantiomer withthe "S" configuration. The racemic mixture is useful in the same way andfor the same purpose as the pure S-enantiomer; the difference is thattwice as much racemic material must be used to produce the same effectas the pure S-enantiomer. If desired, the mixture of enantiomers isresolved by means known to those skilled in the art. It is preferable toresolve the racemic mixture at the stage of the amino compounds (XI)using methods known to those skilled in the art, see for example,Optical Remixture Procedures for Chemical Compounds, Vol 1,: Amines andRelated Compounds, Paul Newman, Optical Remixure Information Center,Manhattan College, Riverdale, N.Y., 10471, 1978. For example, treatmentof the d,l-amino mixture (XI) with an optically active acid such as(+)-tartaric acid or alternatively with (-)-tartaric acid, would yield amixture of diastereomeric salts, which can be separated mostconveniently by fractional crystallization to give a salt containingonly one enantiomer of the racemic mixture. Other suitable opticallyactive acids include, (-) dibenzoyltartaric acid, (+)-camphoric acid,(+)- and (-)-malic acid and (+)-camphor-10-sulfonic acid. By reactingthe diastereomeric salt with a base one obtains the enantiomer as thefree amino compound (XI). These optically pure compounds are then usedin the same way as the racemic mixture.

Charts D and E depict alternative and preferred routes toenantiomerically enriched substituted aryl- andheteroarylphenyloxazolidinones of formula XII which are the subject ofthis invention. It will be apparent to those skilled in the art thatthese are merely representative examples, and that slight modificationsof the provided synthetic protocols will allow for the preparation offurther enantiomerically enriched examples of the oxazolidinones of theinvention. The reaction of an isocyanate with racemic andenantiomerically enriched glycidol derivatives to give oxazolidinones isa known and facile process. (See e.g., Tetrahedron Letter, 809 (1971);J. Med. Chem., 32, 1673 (1989); J. Med. Chem., 33, 2569 (1990); J. Med.Chem., 35, 1156 (1992); U.S. Pat. No. 4,705,799 (1987)). As shown inChart D, an isocyanate of structure (1) can be reacted with commerciallyavailable (R)-glycidyl butyrate (see, e.g., W. E. Ladner, G. M.Whitesides; J. Am. Chem. Soc., 106: 7250 (1984), available from AldrichChemical Company, Inc.) in the presence of catalytic lithium bromide andtributyl-phosphine oxide and in a suitbable solvent such as xylene andat a suitable temperatur (e.g. reflux) to provide the oxazolidinoneintermediate (2). The butyryl group is then removed by reaction with analkoxide, preferably sodium methoxide in methanol, to furnish the keyhydroxymethyloxazolidinone intermediate (3). The most preferred route tothe alcohol (3) involves the deprotonation of an appropriateCBz-protected aniline of structure (4), readily prepared by standardSchotten-Baumann conditions or other variations known to one skilled inthe art, with a suitable base such as n-butyllithium in a suitablesolvent such as tetrahydrofuran and at a suitable temperature such as-78° to -60°. Addition of the (R)-glycidyl butyrate, followed by warmingto ambient temperature, then directly affords thehydroxymethyloxazolidinone (3), identical in all respects with materialprepared via the isocyanate sequence. Compound (3) is then converted tothe corresponding methanesulfonate (mesylate) or p-toluenesulfonate(tosylate) derivative (5) or the like, by the action of methanesulfonylchloride/pyridine or methanesulfonylchloride/triethylamine/dichloromethane orp-toluenesulfonylchloride/pyridine. The resultant sulfonate is then reacted with an azidesource, for example sodium or potassium azide, in a dipolar aproticsolvent such as N,N-dimethylformamide (DMF) or 1-methyl-2-pyrrolidinoneoptionally in the presence of a catalyst such as 18-crown-6 at atemperature of 50° to 90° to afford the azide (6). The azide (6) is thenreduced by hydrogenation with palladium on carbon or a platinum-basedcatalyst in an appropriate solvent such as ethyl acetate or methanol (orcombina-tions thereof) to give the aminomethyloxazolidinone (7).Alternatively, the azide may be reduced by treatment with a trivalentphosphorus compound such as triphenylphosphine in the presence of waterand in a suitable solvent such as tetrahydrofuran (THF). Compound (7) isthen acylated by reactions known to those skilled in the art to give theintermediates of structure (8). Compound (8) is then iodinated withiodine monochloride in acetic acid or acetic acid/trifluoroacetic acid(see, e.g., U.S. Pat. No. 4,705,799 (1987)) at a temperature from 0° to70° or with iodine and silver trifluoro-acetate (see e.g., J. Med.Chem., 33, 2569 (1990); and J. Med. Chem., 35, 1156 (1992)) to furnishthe enantiomerically enriched substituted iodophenyloxazolidinoneintermediate (9). Alternatively, (8) can be brominated withN-bromosuccinimide to give the corresponding bromophenyl- oxazolidinoneof structure 9.

Further elaboration of the intermediates of formula (9) to make theenantiomerically enriched substituted aryl- andheteroarylphenyloxazolidinones of formula XII which are the subject ofthis invention is outlined in Chart E. Compound (9) is reacted with thedesired aryl- or heteroaryl-substituted metal of formula R³ M(M=trialkyltin, boronic acid or ester, or halozinc) in the presence of asuitable palladium catalyst such astetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium chloride in a suitable solvent such asDMF or 1,4-dioxane at a suitable temperature (typically 70°-100° C.) toafford the coupled aryl- or heteroarylphenyloxa-zolidinone products ofstructure XII. Alternatively, the iodo- or bromophenyloxazolidinone offormula (9) is converted to the corresponding trimethyltin derivative(11) by treating it with hexa-methylditin in the presence of a suitablepalladium catalyst such as tetrakis(triphenylphosphine)-palladium orbis(triphenylphosphine)palladium chloride in a suitable solvent such asDMF or 1,4-dioxane at a suitable temperature (typically 70° to 100° C.).Intermediate (11) is then treated with the desired aryl or heteroarylhalide of formula R³ X (X=Br or I) in the presence of a suitablepalladium catalyst such as tetrakis-(triphenylphosphine)palladium orbis(triphenyl-phosphine)palladium chloride in a suitable solvent such asDMF or 1,4-dioxane at a suitable temperature (typically 70°-100° C.) toafford the enantiomerically enriched aryl- orheteroaryl-phenyloxazolidinone products of structure XII which are thesubject of this invention. This latter route (proceeding through 11) isexemplified in the supplemental experimental section by a racemicExample 55.

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

CONVENTIONS

The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, "Z₁ " or "R_(i) " where "i" is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃ --C(═Z₁)H. Groups R_(i) andR_(j) would represent monovalent variable substituents if attached tothe formula CH₃ --CH₂ --C(R_(i))(R_(j))H₂. When chemical formulas aredrawn in a linear fashion, such as those above, variable substituentscontained in parentheses are bonded to the atom immediately to the leftof the variable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom.

Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol "--" in general representsa bond between two atoms in the chain. Thus, CH₃ --O--CH₂--CH(R_(i))--CH₃ represents a 2-substituted-1-methoxypropane compound.In a similar fashion, the symbol "═" represents a double bond, e.g., CH₂═C(R_(i))--O--CH₃, and the symbol ".tbd." represents a triple bond,e.g., HC.tbd.C--CH(R_(i))--CH₂ --CH₃. Carbonyl groups are represented ineither one of two ways: --CO-- or --C(═O)--, with the former beingpreferred for simplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments canbe represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)--CH═CCl--CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by --N*--(CH₂)₂ --N(C₂ H₅)--CH₂ --C*H₂.

A rigid cyclic (ring) structure for any compounds herein defines anorientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, --C(X₁)(X₂)-- the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is "below" anothersubstituent (X₂) will be identified as being in the alpha (α)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol " - - - " or " . . .". The corresponding substituent attached "above" (X₂) the other (X₁) isidentified as being in the beta (β) configuration and is indicated by anunbroken line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be takentogether or separately or both in the definition of the variable. Forexample, a variable R_(i) attached to a carbon atom as --C(═R_(i))--might be bivalent and be defined as oxo or keto (thus forming a carbonylgroup (--CO--)) or as two separately attached monovalent variablesubstituents α-R_(i-j) and β-R_(i-k). When a bivalent variable, R_(i),is defined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form"α-R_(i-j) :β-R_(i-k) " or some variant thereof. In such a case bothα-R_(i-j) and β-R_(i-k) are attached to the carbon atom to give--C(α-R_(i-j))(β-R_(i-k))--. For example, when the bivalent variable R₆,--C(═R₆)-- is defined to consist of two monovalent variablesubstituents, the two monovalent variable substituents are α-R₆₋₁:β-R₆₋₂, . . . α-R₆₋₉ :β-R₆₋₁₀, etc, giving --C(α-R₆₋₁)(βR₆₋₂)--, . . .--C(α-R₆₋₉)(β-R₆₋₁₀)--, etc. Likewise, for the bivalent variable R₁₁,--C(═R₁₁)--, two monovalent variable substituents are α-R₁₁₋₁ :β-R₁₁₋₂.For a ring substituent for which separate α and β orientations do notexist (e.g. due to the presence of a carbon double bond in the ring),and for a substituent bonded to a carbon atom which is not part of aring the above convention is still used, but the α and β designationsare omitted.

Just as a bivalent variable may be defined as two separate monovalentvariable substituents, two separate monovalent variable substituents maybe defined to be taken together to form a bivalent variable. Forexample, in the formula --C₁ (R_(i))H--C₂ (R_(j))H--(C₁ and C₂ definearbitrarily a first and second carbon atom, respectively) R_(i) andR_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (--O--) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group --X--Y--, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation ". . . R_(i) and R_(j) are taken together to form --CH₂ --CH₂ --O--CO-- .. ." means a lactone in which the carbonyl is bonded to C₂. However,when designated " . . . R_(j) and R_(i) are taken together to form--CO--O--CH₂ --CH₂ -- the convention means a lactone in which thecarbonyl is bonded to C₁.

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as "C₁ -C₄ ", where both "1" and "4" are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, "C₁ -C₄ alkyl" represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂ -C₄ alkoxy-carbonyl describes a group CH₃ --(CH₂)_(n) --O--CO--where n is zero, one or two. By the second method, the carbon atomcontent of only each portion of the definition is indicated separatelyby enclosing the "C_(i) -C_(j) " designation in parentheses and placingit immediately (no intervening space) before the portion of thedefinition being defined. By this optional convention (C₁-C₃)alkoxycarbonyl has the same meaning as C₂ -C₄ alkoxycarbonyl becausethe "C₁ -C₃ " refers only to the carbon atom content of the alkoxygroup. Similarly while both C₂ -C₆ alkoxyalkyl and (C₁ -C₃)alkoxy-(C₁-C₃) alkyl define alkoxyalkyl groups containing from 2 to 6 carbonatoms, the two definitions differ since the former definition allowseither the alkoxy or alkyl portion alone to contain 4 or 5 carbon atomswhile the latter definition limits either of these groups to 3 carbonatoms.

DEFINITIONS

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

Brine refers to an aqueous saturated sodium chloride mixture.

DMF refers to N,N-dimethylformamide.

THF refers to tetrahydrofuran.

CBZ refers to carbobenzyloxy.

n-BuLi refers to n-butyl lithium

SG refers to silica gel.

IR refers to infrared spectroscopy; FTIR refers to Fourier Transform IR.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from tetramethylsilane.

--φ refers to phenyl (C₆ H₅).

MS refers to mass spectrometry expressed as m/e or mass/charge unit.

HRMS refers to high remixture mass spectrometry. M+H!⁺ refers to thepositive ion of a parent plus a hydrogen atom.

EI refers to electron impact.

CI refers to chemical ionization.

FAB refers to fast atom bombardment.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v). When the solubility of a solid in a solvent is usedthe ratio of the solid to the solvent is weight/volume (wt/v).

Stabase refers to a particular protecting group for amines (--NH₂). Thechemical composition is --Si(CH₃)₂ --CH₂ --CH₂ --Si(CH₃)₂ -- and itforms a five member heterocyclic ring, the fifth member is the nitrogenof the amino group.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Preparation 1 N,N- 1,2-Bis(dimethylsilyl)ethane!-3,5-difluoroaniline

Anhydrous THF (135 ml) is added to 3,5-difluoraniline (8.64 g, 66.9mmol) under a nitrogen atmosphere. The resulting mixture is cooled in adry ice-isopropanol bath and stirred. n-Butyl lithium (1.6M in hexanes,88 ml, 141 mmol, 2.1 eq) is added to the reaction mixture. The reactiontemperature is maintained between -70 and -40° during the addition.After an additional 20 min, 1,2-bis(chlorodimethylsilyl)ethane (14.4 g,66.9 mmol, 1 eq) in 135 ml of anhydrous THF is slowly added. Thehomogenous mixture is allowed to stir for an additional 45 min and thenwarmed to 20-25°. The reaction is carefully quenched with water (200 ml)and extracted with ether (4×200 ml). The combined organic phasess arewashed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure to a solid. The crude material is purified bysublimation (5 torr, 40°) to give the title compound, mp 71-72°; FTIR(neat) 2958, 2928, 1626, 1581, 1476, 1453, 1345, 1248 and 995 cm⁻¹ ; MS(EI, m/z) 271, 256, 228 and 73; NMR (CDCl₃) 6.36, 6.29, 0.85 and 0.25 δ.

Preparation 2 4-(3-Pyridyl)-3,5-difluoroaniline

THF (27 ml) is added to N,N-1,2-bis(dimethylsilyl)ethane!-3,5-difluoroaniline (PREPARATION 1, 1.82g, 6.72 mmol) under a nitrogen atmosphere. The resulting mixture iscooled to -70°. To the cold mixture is added n-butyl lithium (1.6M inhexanes, 5.03 ml, 8.06 mmol, 1.2 eq) via a syringe pump (0.12 ml/min).After the addition is complete, the reaction mixture is allowed to stirfor an additional 20 min and then zinc chloride (1.0M in THF, 8.06 ml,8.06 mmol, 1.2 eq) is added. The reaction is warmed to -40° for 15 min.To the reaction mixture is addedtetrakis(triphenylphosphine)palladium(0) (773 mg, 0.672 mmol, 0.10 eq)in THF (50 ml) followed by 3-bromopyridine (647 μl, 6.72 mmol, 1.0 eq).The cooling bath is removed and the reaction is warmed to 20-25°. Thereaction is heated to reflux temperature for 16 hr. After this time, thereaction is quenched with aqueous hydrochloric acid (10%, 100 ml). Theresulting suspension is vigorously stirred for 0.5 hr and then washedwith ether (3×50 ml). The recovered aqueous layer is adjusted to pH 14with 50% sodium hydroxide (aq) and then extracted with (4×50 ml) ether.The combined organic extracts are washed with brine, dried (sodiumsulfate), filtered and concentrated under reduced pressure to give asolid. This crude material is purified by silica gel chromatography (200g of silica gel), eluted with acetonitrile/chloroform (5/95-1 l, 10/90-1l, 15/85-1 l). The appropriate fractions are pooled and concentrated togive the title compound, mp 141-142°; FTIR (mull) cm⁻¹ 3141, 1634, 1460,1164, 1012, 708; MS (EI, m/z) 206, 205, 179, 158 and 89; NMR (CDCl₃) δ8.67, 8.55, 7.75, 7.35, 6.31 and 4.01.

Preparation 3 N-Carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline

4-(3-Pyridyl)-3,5-difluoroaniline (PREPARATION 2, 625 mg, 3.03 mmol),sodium bicarbonate (382 mg, 4.55 mmol, 1.5 eq) and dry THF (60 ml) arecombined. The resulting mixture is placed under an atmosphere ofnitrogen and benzylchloroformate (394 μl, 4.55 mmol, 1.5 eq) is added.The reaction is allowed to stir at 20-25°. After this time, the reactionis added to methylene chloride (150 ml) and washed with saturated sodiumbicarbonate then brine, dried (sodium sulfate), filtered andconcentrated under reduced pressure to a solid which is puried by silicagel chromatography (200 g of silica gel, eluted withacetonitrile/chloroform (3/97-1 l, 5/95-21 l), the title compound isrecovered as a solid, mp 188-190°; FTIR (neat) cm⁻¹ 3030, 1737, 1642,1478, 1408, 1231, 1029, 723; MS (EI, m/z) 340, 296, 232, 205, 91, 79;NMR (CD₃ CL₃) δ 8.59, 8.53-8.51, 7.95-7.92, 7.56-7.51, 7.44×7.31, 7.28and 5.21.

Preparation 4 N-Allyl-N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline

A mixture of N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline(PREPARATION 3, 543 mg, 1.60 mmol) in anhydrous THF (40 ml) is treatedwith sodium hydride (60% dispersion in mineral oil, 128 mg, 3.19 mmol, 2eq). The reaction is kept under an atmosphere of nitrogen at 20-25° for0.5 hr. After this time, ally bromide (691 μl, 7.99 mmol, 5 eq) isadded. Stirring is continued at 20-25° for 16 hr. After this time, thereaction is carefully quenched with water (20 ml). The layers areseparated and the aqueous layer is extracted with ethyl acetate (3×25ml). The combined organics phases are washed with brine, dried (sodiumsulfate), filtered and concentrated under reduced pressure. Theconcentrate is purified by silica gel chromatography (125 g of silicagel) eluting with acetonitrile/chloroform (3/97-1 l). The appropriatefractions are concentrated to give the title compound. An analyticalsample is prepared by preparative TLC (SG, acetonitrile/chloroform-6/94), mp=92-93°; FTIR (mull) cm⁻¹ 3068, 3061, 1710, 1705, 1643, 1635,1412, 1263, 1024, 733; MS (EI) m/z: 380, 336, 309, 245, 91, 65; NMR(CDCl₃) 8.72, 8.62, 7.99, 7.42-7.36, 7.03, 5.94, 5.23-5.18 and 4.34 δ.

Preparation 5 (±)-5-(Iodomethyl)-3-4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone

N-Allyl-N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION4, 496 mg 1.31 mmol) in chloroform (25 ml), pyridine (1.58 ml, 19.6mmol, 15 eq) and iodine (4.97 g, 19.6 mmol, 15 eq) are combined. Theresulting mixture is placed under an atmosphere of nitrogen and heatedto 50° with stirring. After 1.5 hr, the reaction is decanted intochloroform (70 ml). The remaining sludge is rinsed with chloroform (3×15ml). The combined organics are washed with sodium thiosulfate (20%),then brine, dried (sodium sulfate), filtered and concentrated underreduced pressure to give a solid. This material is purified by silicagel chromatography (100 g) eluting with methanol/chloroform (0.5/99.5-1l, 1/99, 1 l). The appropriate fractions are pooled and concentrated togive the title compound, mp 133-134°; FTIR (mull) cm⁻¹ 3130, 1758, 1650,1414, 1241, 1017 and 846; NMR (CDCl₃) 8.72, 8.62, 7.79, 7.43-7.38, 7.32,4.84-4.72, 4.19, 3.80, 3.51 and 3.39 δ.

Preparation 6 (±)-5-(Azidomethyl)-3-4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone

(±)-5-(Iodomethyl)-3- 4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone(PREPARATION 5, 577 mg, 1.31 mmol) in DMF (dried over 4A sieves, 15 ml)is combined with sodium azide (681 mg, 10.5 mmol, 8 eq). The reaction isplaced under an atmosphere of nitrogen and heated to 55°. After 2 hr,the reaction is added to water (100 ml) and then extracted with ethylacetate (4×25 ml). The combined organic extracts are combined and arewashed with water then brine, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The crude azide is suitable forreduction without further purification. An analytical sample is preparedby preparative TLC (silica gel) eluting with acetonitrile/chloroform(10/90). The appropriate fractions are pooled and concentrated to givethe title compound, mp 97-98°; FTIR (mull) cm⁻¹ 3483, 2110, 1746, 1640,1417, 1237, 1064 and 716; MS (EI, m/z) 331, 274, 258, 232, 217, 190 and43; NMR (CDCl₃) 8.72, 8.63, 7.79, 7.42-7.38, 7.34, 4.90-4.82, 4.11,3.88, 3.77 and 3.63 δ.

Preparation 7 (±)-5-(Aminomethyl)-3-4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone

(±)-5-(Azidomethyl)-3- 4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone(PREPARATION 6, 354 mg, ˜1.07 mmol) in methanol (40 ml) and palladium oncarbon (10%, 50 mg) are mixed. The mixture is purged with nitrogen andthen placed under an atmosphere of hydrogen (1 atm). The reaction isallowed to stir at 20-25° for 16 hrs. After this time, the reaction isfiltered and concentrated under reduced pressure to a solid amine. Thecrude amine is suitable for acetylation without further purification. Ananalytical sample is prepared by preparative TLC (SG)methanol/chloroform (10/90). The title compound is recovered as a solid,mp 143-145°; FTIR (neat) cm⁻¹ 3368, 1757, 1646, 1412, 1244, 1025 and714; MS (EI, m/z) 305, 276, 233, 219, 44 and 29; NMR (CDCl₃) 8.71, 8.62,7.79, 7.39, 7.33, 4.79-4.70, 4.06, 3.92, 3.18, 2.98 and 1.52 δ.

Preparation 8 4-(4-pyridyl)-3,5-difluoroaniline

Following the general procedure of PREPARATION 2 and making non-criticalvariations N,N- 1,2-bis(dimethylsilyl)ethane!-3,5-difluoroaniline(PREPARATION 1, 2.00 g 7.38 mmol) is transmetallated and combined withtetrakis(triphenylphosphine)palladium (0) (0.1 eq) and 4-bromopyridine(1 eq). The 4-bromopyridine is freshly prepared from the hydrochloricacid salt as described below. The salt is neutralized in excesssaturated sodium bicarbonate. The free base is then extracted withdiethyl ether. The combined organic extracts are dried over magnesiumsulfate for 15 min, filtered, then concentrated under reduced pressure.The free base is stored in a stoppered flask, under nitrogen and frozenin dry ice prior to use. The free base quickly decomposes at 20-25°. Thereaction is worked up as previously described. The crude product isisolated. The NMR showed this material to be a mixture of desiredproduct and its zinc chloride complex (˜1:1). An analytical sample isprepared by preparative TLC (SG) eluting with acetonitrile/chloform(10/90). NMR (CDCl₃) δ 8.63, 7.38, 6.30 and 4.06.

Preparation 9 N-Carbobenzyloxy-4-(4-pyridyl)-3,5-difluoroaniline

Following the general procedure of PREPARATION 3 and making non-criticalvariations 4-(4-pyridyl)-3,5-difluoroaniline (PREPARATION 8, 236 mg,1.15 mmol) is converted to the carbamate derivative. The crude productis purified by silica gel chromatography (100 g of SG, eluted with a3-5% acetonitrile/chloroform gradient), the title compound is recoveredas a solid, mp 185-186°; FTIR (neat) cm⁻¹ 1743, 1642, 1605, 1254, 1072;HRMS calc'd for C₁₉ H₁₄ F₂ N₂ O₂ =340.1023, found=340.1029; MS (EI, m/z)340, 232, 108, 91, 79, 43; NMR (CDCl₃) δ 8.67, 7.43-7.38, 7.15, 5.23.

Preparation 10N-Allyl-N-carbobenzyloxy-4-(4-pyridyl)-3,5-difluoroaniline

Following the general procedure of PREPARATION 4 and making non-criticalvariations but starting withN-carbobenzyloxy-4-(4-pyridyl)-3,5-difluoroaniline (PREPARATION 9, 468mg, 1.38 mmol) is allylated. The crude product is purified by silica gel(125 g) chromatography eluted with acetonitrile/chloroform (3/97, 2 l).The appropriate fractions are pooled and concentrated to give the titlecompound, mp 82-83°; FTIR (neat) cm⁻¹ 1713, 1635, 1598, 1396, 1312,1235, 1028; MS (EI, m/z) 380 M⁺ !, 330, 246, 219, 91, 40; NMR (CDCl₃)8.69, 7.41-7.33, 7.03, 5.92, 5.25-5.17 and 4.34 δ.

Preparation 11 (±)-5-Iodomethyl-3-4-(4-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone

Following the general procedure of PREPARATION 5 and making non-criticalvariations but starting withN-allyl-N-carbobenzyloxy-4-(4-pyridyl)-3,5-difluoroaniline (PREPARATION10, 241 mg, 0.634 mmol) is converted to the oxazolidinone iodide. Thecrude product is not purified further, NMR (CDCl₃) δ 8.70, 7.44, 7.32,4.85-4.73, 4.19, 3.80, 3.50, 3.40.

Preparation 12 (R)- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methylbutyrate

A mixture of lithium bromide (0.181 g, 2.08 mmol), tri-n-butylphosphineoxide (0.454 g, 2.08 mmol), and dry o-xylene (10 ml) is azeotropicallydried for 1 hr. After cooling below the reflux point, a mixture of(R)-glycidyl butyrate (5.000 g, 34.68 mmol) and 3-fluorophenylisocyanate (4.755 g or 3.96 ml, 34.68 mmol) in dry o-xylene (10 ml) isadded over 10 min to the hot mixture (some refluxing observed during theaddition). When the addition is complete, the mixture is heated toreflux for 2 hr and then allowed to cool to 20-25°. The solvent isremoved under reduced pressure and the residue chromatographed oversilica gel, eluting with hexane/ethyl acetate (6:1, 4:1, and then 2:1),to give the title compound, α!²⁵ _(D) -46.7° (c 1.0, CHCl₃); IR (mineraloil mull) 1758, 1615, 1591, 1498, 1229, 1197, 1169 cm⁻¹ ; NMR (CDCl₃,300 MHz) δ 7.44, 7.34, 7.23, 6.86, 4.88, 4.39, 4.32, 4.13, 3.82, 2.33,1.63, 0.92; MS (m/z) 281, 193, 180, 150, 148, 137, 123, 95, 43; HRMS(m/z) 281.1068 (calc'd for C₁₄ H₁₆ FNO₄ =281.1063).

Preparation 13 (R)-3-(3-fluorophenyl)-5-(hydroxymethyl)-2-oxooxazolidine

A mixture of (R)- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methylbutyrate (PREPARTION 12, 2.789 g, 9.91 mmol) in methanol (10 ml) istreated with a 25 wt. % mixture of sodium methoxide in methanol (57 μl,0.99 mmol) at 20-25°. After 45 min as measured by TLC(methanol/chloroform, 5/95) the starting material has been consumed. Thereaction mixture is carefully quenched by the addition of hydrochloricacid (1N, 0.99 ml, 0.99 mmol) and then concentrated under reducedpressure. Chromatography of the concentrate over silica gel, elutingfirst with hexane/ethyl acetate (1/1), and then ethyl acetate, poolingand concentratig the appropriate fractions gives the title compound, mp106.5-107.5°; α!²⁵ _(D) -66.8° (c 1.1, CH₃ CN); IR (mineral oil mull):3520, 1724, 1612, 1590, 1496, 1428, 1420, 1232 and 1199 cm⁻¹ ; NMR(CDCl₃, 300 MHz) δ 7,44, 7.32, 7.23, 6.84, 4.77, 4.07-3.96, 3.76 and2.44; MS (m/z) 211, 180, 136, 124, 95; HRMS (m/z) 211.0641 (calc'd forC₁₀ H₁₀ FNO₃ : 211.0645).

The enantiomeric excess of the oxazolidinone alcohol is determined byreacting it with (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetic acid(DCC, DMAP, methylene chloride at 20-25°), and examining the NMRspectrum of the resultant Mosher ester. The enantiomeric excess isestimated to be ≧95%.

Preparation 14 (R)-3-(3-fluorophenyl)-5-(hydroxymethyl)-2-oxooxazolidine

A mixture of N-(carbobenzyloxy)-3-fluoroaniline (1.000 g, 4.08 mmol) indry tetrahydrofuran (10 ml) is cooled with a dry ice/acetone bath toabout -78° and then n-butyllithium (1.87 ml of a 1.6M mixture inhexanes, 2.91 mmol) is added. (R)-glycidyl butyrate (0.420 g or 0.413ml, 2.91 mmol) is then added via syringe and the cooling bath allowed todissipate overnight, with the reaction mixture reaching 20-25°. Thereaction mixture is quenched by the careful addition of saturatedaqueous ammonium chloride, the entire mixture transferred to aseparatory funnel with dichloromethane washings, and the mixtureextracted with dichloromethane. The combined organic extracts are driedover sodium sulfate, filtered and concentrated under reduced pressure togive a concentrate which is purified by chromatography over silica gel,eluting with acetonitrile/chloroform (10/90) containing 1% methanol, togive the title compound.

Preparation 15 (R)- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methyl4-methylbenzenesulfonate

A mixture of (R)-3-(3-fluorophenyl)-5-(hydroxymethyl)-2-oxooxazolidine(PREPARATION 14, 1.800 g, 8.52 mmol) in dry pyridine (10 ml) is cooledto 5° and then treated with p-toluenesulfonyl chloride (1.706 g, 8.95mmol). The mixture is left at this temperature overnight. TLC withmethanol/chloroform (5/95) or hexane/ethyl acetate (1/1) indicates thestarting material is consumed. The reaction mixture is dumped into icewater (30 ml) and the resultant precipitate collected by vacuumfiltration through a medium-porosity sintered glass funnel. Thecollected solids are thoroughly washed with cold water, dried underreduced pressure and recrystallized from ethyl acetate/hexane to givethe title compound, mp 114-115°; α!²⁵ _(D) -62.6° (c 1.0, CH₃ CN); IR(mineral oil mull): 1751, 1617, 1591, 1499, 1415, 1362, 1227, 1202,1191, 1172, 1093, 967 cm⁻¹ ; NMR (CDCl₃, 300 MHz) δ 7.78, 7.38, 7.36,7.33, 7.16, 6.86, 4.84, 4.29, 4.24, 4.10, 3.88, 2.46; MS (m/z) 365, 149,122, 91; HRMS (m/z) 365.0738 (calc'd for C₁₇ H₁₆ FNO₅ S: 365.0733).

Preparation 16 (R)- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methyl azide

A mixture of (R)- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methyl4-methylbenzenesulfonate (PREPARATION 15, 2.340 g, 6.40 mmol) in dry DMF(60 ml) is treated with solid sodium azide (3.331 g, 51.23 mmmol) at20-25°. The resultant slurry is warmed to 65° for 4.5 hr and then cooledto 20-25° and left overnight. The reaction mixture is then diluted withethyl acetate and water, transferred to a separatory funnel, andextracted with ethyl acetate. The combined ethyl acetate extracts arewashed thoroughly with water, and then dried (sodium sulfate), filteredand concentrated under reduced pressure to give the title compound, mp81-82°; α!²⁵ _(D) -136.5° (c 0.9, CHCl₃); IR (mineral oil mull): 2115,1736, 1614, 1591, 1586, 1497, 1422, 1233, 1199, 1081, 1049 cm⁻¹ ; NMR(CDCl₃, 300 MHz) δ 7.45, 7.34, 7.23, 6.86, 4.81, 4.09, 3.86, 3.72 and3.60; MS (m/z) 236 (59.0, M⁺), 179, 136, 122, 109, 95, 75; HRMS (m/z)236.0708 (calc'd for C₁₀ H₉ FN₄ O₂ : 236.0709).

Preparation 17 (S)-N-3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methyl!acetamide

A mixture of (R)- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methyl azide(PREPARATION 16, 8.200 g, 34.71 mol) in ethyl acetate (100 ml) istreated with palladium on carbon (10%, 0.820 g) under nitrogen. Theatmosphere is then replaced with hydrogen (balloon) via repeatedevacuation and filling. After stirring under hydrogen for 17 hr, TLC inmethanol/chloroform (5/95) reveals the azide starting material isconsumed. The atmosphere is replaced with nitrogen and then pyridine (6ml) and acetic anhydride (4.1 ml, 43.40 mmol) are added to the reactionmixture. The reaction mixture is stirred for 1 hr at 20-25° and thenfiltered through Celite, washing the pad with ethyl acetate. Thefiltrate is concentrated under reduced pressure and the residue taken-upin dichloromethane. The addition of ether affords a precipitate. Afterstanding in the refrigerator overnight the solids are collected byvacuum filtration, washed with cold hexane, and dried underreducedpressure to give the title compound as a solid. The crude productis purified by chromatography over silica gel, eluting withmethanol/chloroform (5/95). The appropriate fractionsare pooled andconcentrated to give the title compound, mp 140.0-140.5°; α!²⁵ _(D)-6.6° (c 1.0, CHCl₃).

Preparation 18 (S)-N-3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl!methyl!acetamide

(S)-N- 3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl!methyl!- acetamide(PREPARATION 17, 0.280 g, 1.11 mmol) is dissolved in a mixture of aceticacid (20 ml) and trifluoroacetic acid (5 ml) and then treated withiodine monochloride (2.343 g, 14.43 mmol) at 20-25°. The mixture isstirred at 20-25° under nitrogen. After about 24 hr the reaction mixtureis diluted with ether and the solids collected under reduced pressurethrough a medium-porosity sintered glass filter, washing with ether. Thecrude solids are dissolved in hot chloroform (a little methanol isadded), transferred to a separatory funnel, and washed with saturatedaqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine.The organic phase is separated, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound, mp185.5-186.5°; α!²⁵ _(D) -37.6° (c 1.0, DMF).

Preparation 19 (±)-N- 3-3-fluoro-4-(trimethylstannyl)phenyl!-2-oxo-5-oxazolidinyl!-methyl!acetamide

In 1,4-dioxane (10 ml) is combined (±)-N-3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl!methyl!acetamide(PREPARATION 18, 0.091 g, 0.24 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.017 g, 0.024 mmol) and hexamethylditin (0.105 g, 0.321mmol). The reaction mixture is thoroughly purged with nitrogen andheated to reflux temperature for 1.5 hr. After this time, the reactionis concentrated under reduced pressure and then purified by silica gelchromatography (10 g of silica gel; eluted with 100 ml each of 0.5, 1,and finally 1.5% methanol/chloroform). After concentration ofappropriate fractions, the racemic title compound is obtained, mp:127-130°; NMR (CDCl₃, 300 MHz) 7.38-7.33, 7.19, 6.04, 4.83-4.72, 4.05,3.76, 3.71-3.59, 2.02 and 0.34 δ; MS (m/z) 415 (3, M⁺), 401, 25 165,139, 56, 43.

EXAMPLE 1 (±)-5-(Acetamidomethyl)3-4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone

(±)-5-(Aminomethyl)-3- 4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone(PREPARATION 7, 135 mg, 0.433 mmol) in anhydrous methylene chloride (10ml), pyridine (143 μl, 1.77 mmol, 4 eq) and acetic anhydride (167 μl,1.77 mmol, 4 eq) are combined. The reaction is allowed to stir at 20-25°under nitrogen. After 2.5 hr the reaction is added to methylene chloride(30 ml) and washed with saturated sodium bicarbonate then brine, dried(sodium sulfate), filtered and concentrated under reduced pressure to asolid. This material is purified by silica gel (70 g) chromatographyeluted with methanol/chloroform (1/99-4/96 gradient). The appropriatefractions are pooled and concentrated to give the title compound, mp218-219°; FTIR (mull) cm⁻¹ 3347, 1742, 1679, 1648, 1563, 1409, 1247,1022, 755; MS (EI, m/z) 347 M⁺ !, 303, 275, 244, 219, 73, 56; NMR(CDCl₃) 8.68, 8.59, 7.85, 7.48-7.41, 7.31, 4.87-4.79, 4.10, 3.82,3.72-3.57, 2.03 δ.

EXAMPLE 1a (±)-5-(Acetamidomethy)-3-4-(3-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone methanesulfonic acidsalt

(±)-5-(Acetamidomethyl)3-4-(3-pyridyl)!-3,5-difluorophenyl-2-oxazolidinone (EXAMPLE 1, 74 mg,0.21 mmol) and methanesulfonic acid (14 μl , 0.21 mmol) are combined inmethanol (4 ml). The mixture is warmed to reflux temperature for 3 minand the reaction becomes homogeneous. The reaction is cooled to 20-25°and concentrated under reduced pressure to a solid. The solid istriturated with ether and the recovered solid is dissolved in water (8ml), filtered and lyophilized, to give the title compound, mp 203-205°.

EXAMPLE 2 (±)-5-(acetamidomethyl)3-4-(4-pyridyl)!-3,5-difluorophenyl-2-oxazolidinone

(±)-5-Iodomethyl-3- 4-(4-pyridyl)-3,5-difluorophenyl!-2-oxazolidinone(PREPARATION 11, 213 mg) and sodium azide (166 mg, 2.56 mmol, ˜5 eq) arecombined in DMF (10 ml, dried over 4A sieves). The reaction is placedunder an atmosphere of nitrogen and heated to 55°. After 2 hr, thereaction is complete by TLC acetonitrile/methylene chloride (6/94). Thereaction mixture is added to water (50 ml) and extracted with ethylacetate (5×25 ml). The combined organic extracts are washed with water,then brine, dried over sodium sulfate, filtered and concentrated underreduced pressure to an oil (CAUTION: Azides are known to decomposeexplosively). The crude material is combined with methanol (20 ml) andpalladium on carbon (10%, 30 mg). The reaction is purged with nitrogenthen placed under an atmosphere of hydrogen. After 16 hr, the reactionis filtered and concentrated under reduced pressure to a solid. Thismaterial is combined with acetic anhydride (64 μl) and pyridine (55 μl)in methylene chloride (11 ml). The reaction is stirred at 20-25° undernitrogen for 12 hr. After this time, the reaction is added to 50 ml ofmethylene chloride and washed with saturated sodium bicarbonate thenbrine, dried (sodium sulfate), filtered and concentrated under reducedpressure to an oil. The final product is purified by silica gelchromatography (100 g of silica gel, eluting with a methanol/chloroform1-4% gradient). ccc, mp 147-149°; FTIR (neat) cm⁻¹ 1741, 1651, 1646,1412, 1246, 1027, 745; MS (EI, m/z) 347, 303, 243, 219, 206, 58, 29; NMR(CDCl₃) δ 8.70, 7.42, 7.29, 6.10 4.90-4.78, 4.08, 3.82, 3.73-3.67, 2.05.

EXAMPLES 3-54

Following the general procedure of Preparations 1-11 and the aboveEXAMPLES, and (i) starting with the aniline REAGENT (I) listed below foreach example, and (ii) using the appropriate aryl or heteroaryl iodide,bromide, triflate or fluorosulfonate for the palladium-mediated couplingreaction (IV→V), the TITLE COMPOUND for the respective EXAMPLE isobtained.

    ______________________________________    EX-    AM-    PLE  REAGENT   TITLE COMPOUND    ______________________________________    3    3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2,6-dimethylpyridin-         aniline   4-yl)-3,5-difluorophenyl!-2-oxazolidinone    4    3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2-methylpyridin-4-         aniline   yl)-3,5-difluorophenyl!-2-oxazolidinone    5    3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2-ethylpyridin-4-yl)-         aniline   3,5-difluorophenyl!-2-oxazolidinone    6    3,5-difluoro-                   (±)-5-(acetamidomethyl)-3-(4-phenyl-3,5-         aniline   difluorophenyl)-2-oxazolidinone    7    3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(4-         aniline   (dimethylamino)phenyl)-3,5-difluorophenyl!-2-                   oxazolidinone    8    3,5-dichloro-                   (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl)-3,5-         aniline   dichlorophenyl!-2-oxazolidinone    9    3,5-dichloro-                   (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3,5-         aniline   dichlorophenyl!-2-oxazolidinone    10   3,5-dichloro-                   (±)-5-(acetamidomethyl)-3-(4-phenyl-3,5-         aniline   dichlorophenyl)-2-oxazolidinone    11   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    12   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    13   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(2,6-dimethylpyridin-         aniline   4-yl)-3-fluorophenyl!-2-oxazolidinone    14   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(2-methylpyridin-4-         aniline   yl)-3-fluorophenyl!-2-oxazolidinone    15   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(2-ethylpyridin-4-yl)         aniline   3-fluorophenyl!-2-oxazolidinone    16   3-fluoro- (±)-5-(acetamidomethyl)-3-(4-phenyl-3-         aniline   fluorophenyl)-2-oxazolidinone    17   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(4-         aniline   (dimethylamino)phenyl)-3-fluorophenyl!-2-                   oxazolidinone    18   3-chloro- (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl)-3-         aniline   chlorophenyl!-2-oxazolidinone    19   3-chloro- (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3-         aniline   chlorophenyl!-2-oxazolidinone    20   3-chloro- (±)-5-(acetamidomethyl)-3-(4-phenyl-3-         aniline   chlorophenyl)-2-oxazolidinone    21   3,5-bis(tri-                   (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl-3,5-         fluoro-   bis(trifluoromethyl)phenyl!-2-oxazolidinone         methyl)         aniline    22   3,5-bis(tri-                   (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3,5-         fluoro-   bis(trifluoromethyl)phenyl!-2-oxazolidinone         methyl)         aniline    23   3,5-bis(tri-                   (±)-5-(acetamidomethyl)-3- 4-phenyl-3,5-         fluoro-   bis(trifluoromethyl)phenyl!-2-oxazolidinone         methyl)         aniline    24   3-(trifluoro-                   (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl-3-         methyl)-  (trifluoromethyl)phenyl!-2-oxazolidinone         aniline    25   3-(trifluoro-                   (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3-         methyl)-  (trifluoromethyl)phenyl!-2-oxazolidinone         aniline    26   3-(trifluoro-                   (±)-5-(acetamidomethyl)-3- 4-phenyl-3-         methyl)-  (trifluoromethyl)phenyl!-2-oxazolidinone         aniline    27   3,5-dimeth-                   (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl-3,5-         oxyaniline                   dimethoxyphenyl!-2-oxazolidinone    28   3,5-dimeth-                   (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3,5-         oxyaniline                   dimethoxyphenyl!-2-oxazolidinone    29   3,5-dimeth-                   (±)-5-(acetamidomethyl)-3-(4-phenyl-3,5-         oxyaniline                   dimethoxyphenyl)-2-oxazolidinone    30   m-anisidine                   (±)-5-(acetamidomethyl)-3- 4-(3-pyridyl)-3-                   methoxyphenyl!-2-oxazolidinone    31   m-anisidine                   (±)-5-(acetamidomethyl)-3- 4-(4-pyridyl)-3-                   methoxyphenyl!-2-oxazolidinone    32   m-anisidine                   (±)-5-(acetamidomethyl)-3-(4-phenyl-3-                   methoxyphenyl)-2-oxazolidinone    33   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(5-indolyl)-3,5-         aniline   difluorophenyl!-2-oxazolidinone    34   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(3-quinolyl)-3,5-         aniline   difluorophenyl!-2-oxazolidinone    35   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(4-quinolyl)-3,5-         aniline   difluorophenyl!-2-oxazolidinone    36   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(6-quinolyl)-3,5-         aniline   difluorophenyl!-2-oxazolidinone    37   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(4-isoquinolyl)-3,5-         aniline   difluorophenyl!-2-oxazolidinone    38   3,5-difluoro-                   (±)-5-acetamidomethyl)-3- 4-(1-methyl-5-indolyl)-         aniline   3,5-difluorophenyl!-2-oxazolidinone    39   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(6-benzothiazolyl)-         aniline   3,5-difluorophenyl!-2-oxazolidinone    40   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(6-benzoxazolyl)-3,5-         aniline   difluorophenyl!-2-oxazolidinone    41   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2-dimethylamino)-4-         aniline   thiazolyl)-3,5-difluorophenyl!-2-oxazolidinone    42   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2-amino-4-thiazolyl)-         aniline   3,5-difluorophenyl!-2-oxazolidinone    43   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2-(dimethylamino)-         aniline   4-oxazolyl)-3,5-difluorophenyl!-2-oxazolidinone    44   3,5-difluoro-                   (±)-5-(acetamidomethyl)-3- 4-(2-amino-4-oxazolyl)-         aniline   3,5-difluorophenyl!-2-oxazolidinone    45   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(3-quinolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    46   3-fluoro- (±)-5-acetamidomethyl)-3- 4-(4-quinolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    47   3-fluoro- (±)-5-acetamidomethyl)-3- 4-(6-quinolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    48   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(4-isoquinolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    49   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(5-indolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    50   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(1-methyl-5-indolyl)-         aniline   3-fluorophenyl!-2-oxazolidinone    51   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(6-benzothiazolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    52   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(6-benzoxazolyl)-3-         aniline   fluorophenyl!-2-oxazolidinone    53   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(2-amino-4-thiazolyl)-         aniline   3-fluorophenyl!-2-oxazolidinone    54   3-fluoro- (±)-5-(acetamidomethyl)-3- 4-(2-amino-4-oxazolyl)-         aniline   3-fluorophenyl!-2-oxazolidinone    ______________________________________

EXAMPLE 55 (±)-N- 3-3-fluoro-4-(6-quinolyl)phenyl!-2-oxo-5-oxazolidinyl!methyl!acetamide

(±)-N- 3-3-fluoro-4-(trimethylstannyl)phenyl!-2-oxo-5-oxazolidinyl!methyl!acetamide(PREPARATION 19, 0.367 g, 0.88 mmol), 6-bromoquinoline (0.239 g, 1.15mmol) and bis(triphenyl-phosphine)palladium(II) chloride (0.062 g, 0.088mmol) are combined with DMF (10 ml). The reaction mixture is thoroughlypurged with nitrogen and then heated to 80° under nitrogen. After 2 hr,little progress is noted by TLC and so the reaction mixture is heated to95° for a further 2 hr. At this point, TLC revealed the reaction iscomplete. The mixture is cooled to 20-25° and concentrated under reducedpressure to give a crude material which is purified by chromatographyover silica gel (10 g of silica gel; eluted with methanol/chloroform,1→4%) to give the racemic title compound, mp 216-219° (dec); IR(internal reflectance) 3411, 3281, 1743, 1657, 1630, 1566, 1521, 1499,1416, 1226, 1194 cm⁻¹ ; NMR (CDCl₃, 300 MHz) 8.95, 8.26-8.20, 8.00,7.92, 7.61, 7.57, 7.47, 7.35, 6.08, 4.84, 4.13, 3.86, 3.80-3.62, 2.05 δ;MS (m/z) 379 (100.0, M⁺), 335, 307, 276, 264, 251.

EXAMPLE 56 (S)-N- 3-3-fluoro-4-(4-pyridyl)phenyl!-2-oxo-5-oxazolidinyl!methyl!acetamide

A slurry of (±)-N-3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl!methyl!acetamide(PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060g, 0.248 mmol) in 1,4-dioxane (5 ml) is degassed by repeated evacuationand filling with nitrogen. Bis(triphenylphosphine)palladium (II)chloride (0.012 g, 0.0165 mmol) is added, the reaction again degassed,and then the mixture is brought to reflux under nitrogen. After 4 hr TLC(silica gel, 10% methanol/chloroform) reveals some of the iodide stillremains. The mixture is refluxed a further 20 hr, cooled to 20-25°, andconcentrated under reduced pressure. The residue is chromatographed oversilica gel, eluting with a little chloroform and thenmethanol/chloroform (1%, 2%, and then 5%). The appropriate fractions arepooled and concentrated to give the enantiomerically enriched titlecompound, mp 190.5-191.0°; α!²⁵ _(D) -16.40 (c 0.5, CHCl₃). Thefollowing characteristics are noted for a racemic sample, mp 179-180°;IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600,1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm⁻¹ ; NMR (CDCl₃, 300MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62,2.04 δ; MS (m/z) 329 (39.8, M⁺), 285, 257, 201, 172, 73 and 42. ##STR3##

We claim:
 1. A substituted heteroarylphenyl oxazolidinone of formula(XII) where(I) R₁ and R₂ are the same or different and are selected fromthe group consisting of(a) --H, (b) --F, (c) --Cl, (d) --CF₃, and (e)--OCH₃, provided that only one of R₁ or R₂ may be hydrogen; (II) R₃ isselected from the group consisting of(x) thiazolyl, (y) isothiazolyl,(z) oxazolyl, (aa) isoxazolyl, where substituents (x), (y), (z) and (aa)are optionally substituted with X and Y; (III) each occurrence of Y isindependently selected from(a) --H, (b) --F, (c) --Cl, (d) --Br, (e)--I, (f) --R₃₋₁, (g) --OR₃₋₁ where R₃₋₁ is H or C₁ -C₄ alkyl or (h)--NO₂ ; (IV) each occurrence of X is independently selected from(a) --H,(b) C₁ -C₈ alkyl optionally substituted with one or more halogens,--OH,═O other than at alpha position, --S(O)_(n) R₃₋₂ where R₃₋₂ is C₁ -C₄alkyl or C₃ -C₈ cycloalkyl, or --NR₃₋₃ R₃₋₄ where R₃₋₃ and R₃₋₄ are thesame or different and are --H, C₁ -C₈ alkyl, C₃ -C₈ cycloalkyl,--(CH₂)_(t) CHOR₃₋₅, --(CH₂)_(t) NR₃₋₆ R₃₋₇, or taken together are--CH₂)O(CH₂)--, --(CH₂)_(t) CH(CO)R₃₋₈, or --(CH₂)N(R₃₋₈)(CH₂)₂--whereR₃₋₅ is --H or C₁ -C₄ alkyl, or R₃₋₆ and R₃₋₇ are the same ordifferent and are --H, C₁ -C₄ alkyl or taken together are --(CH₂)_(r)--, (c) C₂ -C₅ alkenyl, (d) C₃ -C₈ cycloalkyl, (e) --OR₃₋₃ where R₃₋₃ isas defined above, (f) --CN, (g) --S--(O)_(n) --R₃₋₈ where R₃₋₈ isC₁ -C₄alkyl optionally substituted with one or more halogens,--OH, --CN,--NR₃₋₃ R₃₋₄ where R₃₋₃ and R₃₋₄ are as defined above, --CO₂ R₃₋₅ whereR₃₋₅ is as defined above, C₂ -C₄ alkenyl, --NR₃₋₉ R₃₋₁₀ where R₃₋₉ is--H, C₁ -C₄ alkyl, or C₃ -C₈ cycloalkyl and R₃₋₁₀ is --H, C₁ -C₄ alkyl,C₁ -C₄ alkenyl, C₃ -C₄ cycloalkyl, --OR₃₋₅, or --NR₃₋₆ R₃₋₇ where R₃₋₅,R₃₋₆, and R₃₋₇ are as defined above, --N₃, --NHC(O)R₃₋₁₁ where R₃₋₁₁ isC₁ -C₄ alkyl optionally substituted with one or more halogens, (h)--S(O)₂ --N═S(O)_(p) R₃₋₁₄ R₃₋₁₅ where R₃₋₁₄ and R₃₋₁₅ are the same ordifferent and are C₁ -C₂ alkyl, or taken together are --(CH₂)_(q) --,(i) --S--C(O)--R₃₋₁₁ where R₃₋₁₁ is as defined above, (j) tetrazoly, (k)--NR₃₋₃ R₃₋₄ where R₃₋₃ and R₃₋₄ are as defined above, (l)--N(R₃₋₃)COR₃₋₁₁ where R₃₋₃ and R₃₋₁₁ are as defined above, (m)--N(R₃₋₃)S(O)_(n) R₃₋₁₁ where R₃₋₃ and R₃₋₁₁ are as defined above, (n)--CONR₃₋₃ R₃₋₄ where R₃₋₃ and R₃₋₄ are as defined above, (o) --C(O)R₃ 16where R₃₋₁₆ is--H, C₁ -C₈ alkyl optionally substituted with one or morehalogens, C₁ -C₄ alkyl optionally substituted with--OR₃₋₅, --OC(O)R₃₋₅,--NR₃₋₃ R₃₋₄, --S(O)_(n) R₃₋₁₇, C₃ -C₈ cycloalkyl, or C₂ -C₅ alkenyloptionally substituted with --CHO or --CO₂ R₃₋₅, where R₃₋₃, R₃₋₄, andR₃₋₅ are as defined above and R₃₋₁₇ is C₁ -C₄ alkyl or C₃ -C₈cycloalkyl, (p) --C(═NR₃₋₁₈)R₃₋₁₆ where R₃₋₁₆ is as defined above andR₃₋₁₈ is --NR₃₋₃ R₃₋₄, --OR₃₋₃, or --NHC(O)R₃₋₃ where R₃₋₃ and R₃₋₄ areas defined above, (q) --CR₃₋₁₆ (OR₃₋₁₉)OR₃₋₂₀ where R₃₋₁₆ is as definedabove and R₃₋₁₉ and R₃₋₂₀ are the same or different and are C₁ -C₄alkyl, or taken together are --(CH₂)_(m) --, ##STR4## where R₃₋₃, R₃₋₄,R₃₋₅, R₃₋₉, and R₃₋₁₆ are as defined above and R₃₋₂₁ is R₃₋₄ or --NR₃₋₄R₃₋₅ where R₃₋₄ and R₃₋₅ are as defined above, m is 2 or 3; n is 0, 1,or 2; p is 0 or 1; q is 3, 4 or 5; t is 1, 2 or 3; (V) R₄ is selectedfrom the group consisting of(a) --H, (b) C₁ -C₁₂ alkyl optionallysubstituted with 1-3 Cl, (c) C₃ -C₁₂ cycloalkyl, (d) C₅ -C₁₂ alkenylcontaining one double bond, (e) phenyl optionally substituted with 1-3--OH, --OCH₃, --OC₂ H₅, --NO₂, --F, --Cl, --Br, --COOH and --SO₃ H,--N(R₄₋₁)(R₄₋₂) where R₄₋₁ and R₄₋₂ are the same or different and are--H and C₁ -C₅ alkyl, (f) furanyl, (g) tetrahydrofaranyl, (h)2-thiophene, (i) pyrrolidinyl, (j) pyridinyl, (k) --O--R₄₋₃ where R₄₋₃is C₁ -C₄ alkyl, (l) --NH₂, (m) --NHR₄₋₄ where R₄₋₄ is C₁ -C₃ alkyl or--φ, (n) --NR₄₋₄ R₄₋₅ where R₄₋₄ is as defined above and R₄₋₅ is C₁ -C₃alkyl, or taken together with the attached nitrogen atom to form asaturated mono-nitrogen C₅ -C₇ heterocyclic ring including --O--(morpholine), (o) --CH₂ --OH, (p) --CH₂ --OR₄₋₆ where R₄₋₆ is C₁ -C₄alkyl or --CO--R₄ 7 where R₄₋₇ is C₁ -C₄ alkyl or --φ; andpharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 where one of R₁ or R₂ are hydrogen.
 3. A compound according toclaim 2 where R₃ is thiazolyl or oxazolyl optionally substituted with Xand Y.
 4. A compound according to claim 3 whichis(±)-5-(acetamidomethyl)-3-4-(2-amino-4-thiazolyl)-3-fluorophenyl!-2-oxazolidinone, and(±)-5-(acetamidomethyl)-3-4-(2-amino-4-oxazolyl)-3-fluorophenyl!-2-oxazolidinone.
 5. A compoundaccording to claim 1 where R₁ and R₂ are other than hydrogen.
 6. Acompound according to claim 5 where R₃ is thiazolyl or oxazolyloptionally substituted with X and Y.
 7. A compound according to claim 6which is(±)-5-(acetamidomethyl)-3-4-(2-dimethylamino)-4-thiazolyl)-3,5-difluorophenyl!-2-oxazolidinone,(±)-5-(acetamidomethyl)-3-4-(2-amino-4-thiazolyl)-3,5-difluorophenyl!-2-oxazolidinone,(±)-5-acetamidomethyl)-3-4-(2-(dimethylamino)-4-oxazolyl)-3,5-difluorophenyl!-2oxazolidinone, and(±)-5-(acetamidomethyl)-3-4-(2-amino-4-oxazolyl)-3,5-difluorophenyl!-2-oxazolidinone.